Demonstration of a potent RET transcriptional inhibitor for the treatment of medullary thyroid carcinoma based on an ellipticine derivative

International Journal of Oncology
Vishnu Muthuraj Kumarasamy, Daekyu Sun

Abstract

Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene. In the present study, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Circular dichroism (CD) spectroscopic studies revealed that the incorporation of a piperidine ring in an ellipticine derivative, NSC311153 improves its binding with the G-quadruplex structure and the stability induced by this compound is more potent than ellipticine. Furthermore, this compound also interfered with the transcriptional mechanism of the RET gene in an MTC derived cell line, TT cells and significantly decreased the endogenous RET protein expression. We demonstrated the sp...Continue Reading

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Citations

Jan 20, 2018·Endocrine-related Cancer·Sara RedaelliLuca Mologni
Jan 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zhi-Yin SunTian-Miao Ou
Aug 31, 2021·Cellular and Molecular Life Sciences : CMLS·Fang-Yuan TengYong Xu

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Datasets Mentioned

BETA
GTX102643

Methods Mentioned

BETA
surgical resection
xenograft
PCR
electrophoresis
Assay
footprinting
xenografts
transfection

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